1. Field of the Invention
The present invention relates to a method for producing the derivatives of an inhibtor of Angiotensin Converting Enzyme.
2. Related Prior Art
Being an important medicine for hypertension, ACE inhibitor is significantly developed.
U.S. Pat. No. 4,716,235 mentioned a process for preparing Enalapril in aqueous phase. In this process, L-Proline was first dissolved in alkali aqueous solution to form an amino acid salt, which was then reacted with N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine-N-carboxyanhydride (NEPA-NCA)/acetone to perform a Coupling Reaction. After NEPA-NCA was completely reacted, HCl(aq) was added to adjust the pH of the solution to 4.2. Next, acetone was removed by concentration, and the solution was extracted with a large amount of ethyl acetate three times, and dried with sodium sulfate. Unpurified Enalapril Maleate was finally obtained by filtration, concentration, being heated in acetonitrile, and mixing with maleic acid previously dissolved in heated acetonitrile.
U.S. Pat. No. 5,869,671 also mentioned a method for preparing Enalapril, in which silylated amino acid derived from L-Proline is first dissolved in an organic solvent and then reacted with NEPA-Acid chloride at a temperature lower than xe2x88x9210xc2x0 C. After complete reaction, unpurified Enalapril Maleate can be obtained by adding water, adjusting pH to 3 with 3M HCl(aq), extracting with a large amount of dichloromethane three times, drying with sodium sulfate, filtering, concentrating and adding to maleic acid solution.
U.S. Pat. No. 5,359,086 mentioned another method for preparing Enalapril, in which L-Proline and chlorotrimethylsilane (TMSCl) were mixed to form a silylatedamino acid hydrochloric salt. Next, NEPA was dissolved in dichloromethane of xe2x88x925xc2x0 C. without organic alkali, and then N,N-carbonyldimidazole was added to perform a reaction at 0-5xc2x0 C. for 3 hours. The above silylatedylated amino acid hydrochloric salt solution is then added to continue the reaction at 0-5xc2x0 C. After the reaction is completed, dichloromethane is removed by vaporization, and water and ethyl acetate are added. The solution is then adjusted to pH 8.7 with 50% NaOH(aq), and extracted with ethyl acetate twice. The final product, unpurified Enalapril Maleate can be obtained by adding NaCl to aqueous phase to saturation, adding ethyl acetate, adjusting pH to 4.2 with 18% HCl(aq), extracting, drying with sodium sulfate, filtering, concentrating and adding maleic acid.
In these prior arts, acidic or alkaline aqueous reagents were used for reaction, and therefore more by-product were generated as shown in the following scheme (A). As a result, these processes had lower yield and more complicate operation was needed. Accordingly, the present invention provides an improved method to have higher yield. 
An object of the present invention is to provide a method for producing an angiotensin converting enzyme inhibitor, in which by-product is minimized and yield and purity are improved.
Another object of the present invention is to provide a method for producing an angiotensin converting enzyme inhibitor, which can be easily carried out and achieved in short time.
The method of the present invention includes steps of preparing a compound of the following formula (I) and pharmaceutically acceptable salts thereof, preferably hydrochloric salts and maleate, which is capable of inhibiting ACE. 
wherein R is selected from: 
In the present invention, a method for producing a compound of the formula (I) and pharmaceutically acceptable salts thereof primarily includes a de-protective reaction of silyl group of a compound of the following (II) in non-aqueous medium. 
wherein R1 is selected from: 
The non-aqueous medium aforementioned usually includes at least one organic solvent, which can be methanol, ethanol, 1-propanol, isopropanol, butanol, isobutanol, nbutanol, pentanol or butenediol.
The temperature for carrying out de-protective reaction of silyl group is not restricted, usually at 0xc2x0 C.-60xc2x0 C., and preferably at 5xc2x0 C.-40xc2x0 C.
The compound of the formula (II) can be obtained by reacting a compound of the following formula (III) 
with a compound of the following formula (IV)
Hxe2x80x94R1xe2x80x83xe2x80x83(IV),
wherein R1 is defined as the compound of the formula (II), in an aprotic solvent.
The aprotic solvent aforementioned usually includes at least one organic solvent, for example, butanedione, methyl ethyl ketone, acetonitrile, butyl nitrile, butyl dinitrile, ethyl ether, methyl ether, ethyl methyl ether, tetrahydrofuran, 1,4-dioxane, dichloromethane, dichloroethane, ethyl acetate or methyl acetate.
The temperature for producing the compound of the formula (II) is not restricted, and preferably at 20xc2x0 C.-45xc2x0 C.
The compound of the formula (III) used in the present invention can be referred to U.S. Pat. No. 6,262,274.
The compound of the formulae (IV) can be prepared by reacting an amino acid of the following formula (V)
Hxe2x80x94Rxe2x80x83xe2x80x83(V)
wherein R is defined as above, with a silylated compound in an aprotic solvent.
The amino acid of the formula (V) can be as the follows, 
wherein L-Proline, (S)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid and (S,S,S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid are preferred.
The silylated compound can be. N,Nxe2x80x2-bis(trimethylsily)urea (BSU), Hexamethylsilazanc (HMDS), chlorotrimethylsilane (TMSCl) or bis(trimethylsily)acetamide (BSA).
The aprotic solvent usually includes at least one organic solvent, for example, butanedione, methyl ethyl ketone, acetonitrile, butyl nitrile, butyl dinitrile, ethyl ether, methyl ether, ethyl methyl ether, tetrahydrofuran, 1,4-dioxane, dichloromethane, dichloroethane, ethyl acetate and methyl acetate.
The method for producing the compound of the formula (IV) can further include an organic alkali. For example, aliphatic amine can be added in a reaction of chlorotrimethylsilane and Proline to neutralize HCl generated during this reaction. The aliphatic amine can be methylamines, ethylamines such as triethylamine, phenylethylamine, diethylamine and deritatives thereof, propylamines, butanediamines, etc., wherein ethylamines are preferred.
The present invention characterizes in the one-pot reaction, that is, no separation procedure is necessary and the final pure product can be obtained in the only reactor. In such process, by-product is minimized and complicated purification is avoided.